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| [PMID]: | 27020609 |
| [Au] Autor: | Moyer BJ; Rojas IY; Kerley-Hamilton JS; Hazlett HF; Nemani KV; Trask HW; West RJ; Lupien LE; Collins AJ; Ringelberg CS; Gimi B; Kinlaw WB; Tomlinson CR |
| [Ad] Endereço: | Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Dartmouth Hitchcock Medical Center, One Medical Center Drive, Lebanon, NH 03756, United States. |
| [Ti] Título: | Inhibition of the aryl hydrocarbon receptor prevents Western diet-induced obesity. Model for AHR activation by kynurenine via oxidized-LDL, TLR2/4, TGFß, and IDO1. |
| [So] Source: | Toxicol Appl Pharmacol;300:13-24, 2016 Jun 01. | | [Is] ISSN: | 1096-0333 |
| [Cp] País de publicação: | United States |
| [La] Idioma: | eng |
| [Ab] Resumo: | Obesity is an increasingly urgent global problem, yet, little is known about its causes and less is known how obesity can be effectively treated. We showed previously that the aryl hydrocarbon receptor (AHR) plays a role in the regulation of body mass in mice fed Western diet. The AHR is a ligand-activated nuclear receptor that regulates genes involved in a number of biological pathways, including xenobiotic metabolism and T cell polarization. This study was an investigation into whether inhibition of the AHR prevents Western diet-based obesity. Male C57Bl/6J mice were fed control and Western diets with and without the AHR antagonist α-naphthoflavone or CH-223191, and a mouse hepatocyte cell line was used to delineate relevant cellular pathways. Studies are presented showing that the AHR antagonists α-naphthoflavone and CH-223191 significantly reduce obesity and adiposity and ameliorates liver steatosis in male C57Bl/6J mice fed a Western diet. Mice deficient in the tryptophan metabolizing enzyme indoleamine 2,3-dioxygenase 1 (IDO1) were also resistant to obesity. Using an AHR-directed, luciferase-expressing mouse hepatocyte cell line, we show that the transforming growth factor ß1 (TGFß1) signaling pathway via PI3K and NF-κB and the toll-like receptor 2/4 (TLR2/4) signaling pathway stimulated by oxidized low-density lipoproteins via NF-κB, each induce luciferase expression; however, TLR2/4 signaling was significantly reduced by inhibition of IDO1. At physiological levels, kynurenine but not kynurenic acid (both tryptophan metabolites and known AHR agonists) activated AHR-directed luciferase expression. We propose a hepatocyte-based model, in which kynurenine production is increased by enhanced IDO1 activity stimulated by TGFß1 and TLR2/4 signaling, via PI3K and NF-κB, to perpetuate a cycle of AHR activation to cause obesity; and inhibition of the AHR, in turn, blocks the cycle's output to prevent obesity. The AHR with its broad ligand binding specificity is a promising candidate for a potentially simple therapeutic approach for the prevention and treatment of obesity and associated complications. |
| [Mh] Termos MeSH primário: |
Compostos Azo/farmacologia
Dieta Ocidental
Cinurenina/biossíntese
Obesidade/prevenção & controle
Pirazóis/farmacologia
Receptores de Hidrocarboneto Arílico/antagonistas & inibidores
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| [Mh] Termos MeSH secundário: |
Adiposidade
Animais
Benzoflavonas/farmacologia
Fígado Gorduroso/prevenção & controle
Hepatócitos/efeitos dos fármacos
Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo
Gordura Intra-Abdominal/efeitos dos fármacos
Lipídeos/sangue
Lipoproteínas LDL
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Transdução de Sinais
Receptor 2 Toll-Like/metabolismo
Fator de Crescimento Transformador beta/metabolismo
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| [Pt] Tipo de publicação: | JOURNAL ARTICLE |
[Nm] Nome de substância:
| 0 (2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide); 0 (Azo Compounds); 0 (Benzoflavones); 0 (IDO1 protein, mouse); 0 (Indoleamine-Pyrrole 2,3,-Dioxygenase); 0 (Lipids); 0 (Lipoproteins, LDL); 0 (Pyrazoles); 0 (Receptors, Aryl Hydrocarbon); 0 (Toll-Like Receptor 2); 0 (Transforming Growth Factor beta); 0 (oxidized low density lipoprotein); 343-65-7 (Kynurenine); 604-59-1 (alpha-naphthoflavone) |
| [Em] Mês de entrada: | 1705 |
| [Cu] Atualização por classe: | 170801 |
[Lr] Data última revisão:
| 170801 |
| [Sb] Subgrupo de revista: | IM |
| [Da] Data de entrada para processamento: | 160330 |
| [St] Status: | MEDLINE |
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